SUMO Modulation of Protein Aggregation and Degradation
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Isoform-Specific Monobody Inhibitors of Small Ubiquitin-Related Modifiers Engineered Using Structure-Guided Library Design
Isoform-specific monobody inhibitors of small ubiquitin-related modifiers engineered using structure-guided library design Ryan N. Gilbretha, Khue Truongb, Ikenna Madub, Akiko Koidea, John B. Wojcika, Nan-Sheng Lia, Joseph A. Piccirillia,c, Yuan Chenb, and Shohei Koidea,1 aDepartment of Biochemistry and Molecular Biology, and cDepartment of Chemistry, University of Chicago, 929 East 57th Street, Chicago, IL 60637; and bDepartment of Molecular Medicine, Beckman Research Institute of the City of Hope, 1450 East Duarte Road, Duarte, CA 91010 Edited by David Baker, University of Washington, Seattle, WA, and approved March 16, 2011 (received for review February 10, 2011) Discriminating closely related molecules remains a major challenge which SUMOylation alters protein function appears to be in the engineering of binding proteins and inhibitors. Here we through SUMO-mediated interactions with other proteins con- report the development of highly selective inhibitors of small ubi- taining a short peptide motif known as a SUMO-interacting motif quitin-related modifier (SUMO) family proteins. SUMOylation is (SIM) (4, 7, 8). involved in the regulation of diverse cellular processes. Functional There are few inhibitors of SUMO/SIM interactions, a defi- differences between two major SUMO isoforms in humans, SUMO1 ciency that limits our ability to finely dissect SUMO biology. In and SUMO2∕3, are thought to arise from distinct interactions the only reported example of such an inhibitor, a SIM-containing mediated by each isoform with other proteins containing SUMO- linear peptide was used to inhibit SUMO/SIM interactions, estab- interacting motifs (SIMs). However, the roles of such isoform- lishing their importance in coordinating DNA repair by nonho- specific interactions are largely uncharacterized due in part to the mologous end joining (9). -
Roles of Ubiquitination and Sumoylation in the Regulation of Angiogenesis
Curr. Issues Mol. Biol. (2020) 35: 109-126. Roles of Ubiquitination and SUMOylation in the Regulation of Angiogenesis Andrea Rabellino1*, Cristina Andreani2 and Pier Paolo Scaglioni2 1QIMR Berghofer Medical Research Institute, Brisbane City, Queensland, Australia. 2Department of Internal Medicine, Hematology and Oncology; University of Cincinnati, Cincinnati, OH, USA. *Correspondence: [email protected] htps://doi.org/10.21775/cimb.035.109 Abstract is tumorigenesis-induced angiogenesis, during Te generation of new blood vessels from the which hypoxic and starved cancer cells activate existing vasculature is a dynamic and complex the molecular pathways involved in the formation mechanism known as angiogenesis. Angiogenesis of novel blood vessels, in order to supply nutri- occurs during the entire lifespan of vertebrates and ents and oxygen required for the tumour growth. participates in many physiological processes. Fur- Additionally, more than 70 diferent disorders have thermore, angiogenesis is also actively involved been associated to de novo angiogenesis including in many human diseases and disorders, including obesity, bacterial infections and AIDS (Carmeliet, cancer, obesity and infections. Several inter-con- 2003). nected molecular pathways regulate angiogenesis, At the molecular level, angiogenesis relays on and post-translational modifcations, such as phos- several pathways that cooperate in order to regulate phorylation, ubiquitination and SUMOylation, in a precise spatial and temporal order the process. tightly regulate these mechanisms and play a key In this context, post-translational modifcations role in the control of the process. Here, we describe (PTMs) play a central role in the regulation of these in detail the roles of ubiquitination and SUMOyla- events, infuencing the activation and stability of tion in the regulation of angiogenesis. -
BC-Box Protein Domain-Related Mechanism for VHL Protein Degradation
BC-box protein domain-related mechanism for VHL protein degradation Maria Elena Pozzebona,1,2, Archana Varadaraja,1, Domenico Mattoscioa, Ellis G. Jaffrayb, Claudia Miccoloa, Viviana Galimbertic, Massimo Tommasinod, Ronald T. Hayb, and Susanna Chioccaa,3 aDepartment of Experimental Oncology, European Institute of Oncology, 20139 Milan, Italy; cSenology Division, European Institute of Oncology, 20141 Milan, Italy; dInternational Agency for Research on Cancer, World Health Organization, 69372 Lyon, France; and bCentre for Gene Regulation and Expression, University of Dundee, Dundee DD1 5EH, United Kingdom Edited by William G. Kaelin, Jr., Harvard Medical School, Boston, MA, and approved September 23, 2013 (received for review June 18, 2013) The tumor suppressor VHL (von Hippel–Lindau) protein is a sub- effects of the wild-type Gam1 protein (18, 20, 21), supporting the strate receptor for Ubiquitin Cullin Ring Ligase complexes (CRLs), idea that these effects may depend on Gam1 ability to act as containing a BC-box domain that associates to the adaptor Elongin substrate-receptor protein. B/C. VHL targets hypoxia-inducible factor 1α to proteasome- VHL (von Hippel–Lindau) protein is a cellular BC box-con- dependent degradation. Gam1 is an adenoviral protein, which also taining substrate receptor and associates with Cullin2-based E3 possesses a BC-box domain that interacts with the host Elongin B/C, ligases (22–24). VHL is a tumor suppressor, and its loss leads to – thereby acting as a viral substrate receptor. Gam1 associates with the von Hippel Lindau syndrome that often develops into renal both Cullin2 and Cullin5 to form CRL complexes targeting the host clear-cell carcinoma and other highly vascularized tumors (25, 26). -
Supplementary Table S5. Differentially Expressed Gene Lists of PD-1High CD39+ CD8 Tils According to 4-1BB Expression Compared to PD-1+ CD39- CD8 Tils
BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance Supplemental material placed on this supplemental material which has been supplied by the author(s) J Immunother Cancer Supplementary Table S5. Differentially expressed gene lists of PD-1high CD39+ CD8 TILs according to 4-1BB expression compared to PD-1+ CD39- CD8 TILs Up- or down- regulated genes in Up- or down- regulated genes Up- or down- regulated genes only PD-1high CD39+ CD8 TILs only in 4-1BBneg PD-1high CD39+ in 4-1BBpos PD-1high CD39+ CD8 compared to PD-1+ CD39- CD8 CD8 TILs compared to PD-1+ TILs compared to PD-1+ CD39- TILs CD39- CD8 TILs CD8 TILs IL7R KLRG1 TNFSF4 ENTPD1 DHRS3 LEF1 ITGA5 MKI67 PZP KLF3 RYR2 SIK1B ANK3 LYST PPP1R3B ETV1 ADAM28 H2AC13 CCR7 GFOD1 RASGRP2 ITGAX MAST4 RAD51AP1 MYO1E CLCF1 NEBL S1PR5 VCL MPP7 MS4A6A PHLDB1 GFPT2 TNF RPL3 SPRY4 VCAM1 B4GALT5 TIPARP TNS3 PDCD1 POLQ AKAP5 IL6ST LY9 PLXND1 PLEKHA1 NEU1 DGKH SPRY2 PLEKHG3 IKZF4 MTX3 PARK7 ATP8B4 SYT11 PTGER4 SORL1 RAB11FIP5 BRCA1 MAP4K3 NCR1 CCR4 S1PR1 PDE8A IFIT2 EPHA4 ARHGEF12 PAICS PELI2 LAT2 GPRASP1 TTN RPLP0 IL4I1 AUTS2 RPS3 CDCA3 NHS LONRF2 CDC42EP3 SLCO3A1 RRM2 ADAMTSL4 INPP5F ARHGAP31 ESCO2 ADRB2 CSF1 WDHD1 GOLIM4 CDK5RAP1 CD69 GLUL HJURP SHC4 GNLY TTC9 HELLS DPP4 IL23A PITPNC1 TOX ARHGEF9 EXO1 SLC4A4 CKAP4 CARMIL3 NHSL2 DZIP3 GINS1 FUT8 UBASH3B CDCA5 PDE7B SOGA1 CDC45 NR3C2 TRIB1 KIF14 TRAF5 LIMS1 PPP1R2C TNFRSF9 KLRC2 POLA1 CD80 ATP10D CDCA8 SETD7 IER2 PATL2 CCDC141 CD84 HSPA6 CYB561 MPHOSPH9 CLSPN KLRC1 PTMS SCML4 ZBTB10 CCL3 CA5B PIP5K1B WNT9A CCNH GEM IL18RAP GGH SARDH B3GNT7 C13orf46 SBF2 IKZF3 ZMAT1 TCF7 NECTIN1 H3C7 FOS PAG1 HECA SLC4A10 SLC35G2 PER1 P2RY1 NFKBIA WDR76 PLAUR KDM1A H1-5 TSHZ2 FAM102B HMMR GPR132 CCRL2 PARP8 A2M ST8SIA1 NUF2 IL5RA RBPMS UBE2T USP53 EEF1A1 PLAC8 LGR6 TMEM123 NEK2 SNAP47 PTGIS SH2B3 P2RY8 S100PBP PLEKHA7 CLNK CRIM1 MGAT5 YBX3 TP53INP1 DTL CFH FEZ1 MYB FRMD4B TSPAN5 STIL ITGA2 GOLGA6L10 MYBL2 AHI1 CAND2 GZMB RBPJ PELI1 HSPA1B KCNK5 GOLGA6L9 TICRR TPRG1 UBE2C AURKA Leem G, et al. -
Serum Albumin OS=Homo Sapiens
Protein Name Cluster of Glial fibrillary acidic protein OS=Homo sapiens GN=GFAP PE=1 SV=1 (P14136) Serum albumin OS=Homo sapiens GN=ALB PE=1 SV=2 Cluster of Isoform 3 of Plectin OS=Homo sapiens GN=PLEC (Q15149-3) Cluster of Hemoglobin subunit beta OS=Homo sapiens GN=HBB PE=1 SV=2 (P68871) Vimentin OS=Homo sapiens GN=VIM PE=1 SV=4 Cluster of Tubulin beta-3 chain OS=Homo sapiens GN=TUBB3 PE=1 SV=2 (Q13509) Cluster of Actin, cytoplasmic 1 OS=Homo sapiens GN=ACTB PE=1 SV=1 (P60709) Cluster of Tubulin alpha-1B chain OS=Homo sapiens GN=TUBA1B PE=1 SV=1 (P68363) Cluster of Isoform 2 of Spectrin alpha chain, non-erythrocytic 1 OS=Homo sapiens GN=SPTAN1 (Q13813-2) Hemoglobin subunit alpha OS=Homo sapiens GN=HBA1 PE=1 SV=2 Cluster of Spectrin beta chain, non-erythrocytic 1 OS=Homo sapiens GN=SPTBN1 PE=1 SV=2 (Q01082) Cluster of Pyruvate kinase isozymes M1/M2 OS=Homo sapiens GN=PKM PE=1 SV=4 (P14618) Glyceraldehyde-3-phosphate dehydrogenase OS=Homo sapiens GN=GAPDH PE=1 SV=3 Clathrin heavy chain 1 OS=Homo sapiens GN=CLTC PE=1 SV=5 Filamin-A OS=Homo sapiens GN=FLNA PE=1 SV=4 Cytoplasmic dynein 1 heavy chain 1 OS=Homo sapiens GN=DYNC1H1 PE=1 SV=5 Cluster of ATPase, Na+/K+ transporting, alpha 2 (+) polypeptide OS=Homo sapiens GN=ATP1A2 PE=3 SV=1 (B1AKY9) Fibrinogen beta chain OS=Homo sapiens GN=FGB PE=1 SV=2 Fibrinogen alpha chain OS=Homo sapiens GN=FGA PE=1 SV=2 Dihydropyrimidinase-related protein 2 OS=Homo sapiens GN=DPYSL2 PE=1 SV=1 Cluster of Alpha-actinin-1 OS=Homo sapiens GN=ACTN1 PE=1 SV=2 (P12814) 60 kDa heat shock protein, mitochondrial OS=Homo -
SUMO and Ubiquitin in the Nucleus: Different Functions, Similar Mechanisms?
Downloaded from genesdev.cshlp.org on September 28, 2021 - Published by Cold Spring Harbor Laboratory Press REVIEW SUMO and ubiquitin in the nucleus: different functions, similar mechanisms? Grace Gill1 Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA The small ubiquitin-related modifier SUMO posttrans- tin, SUMO modification regulates protein localization lationally modifies many proteins with roles in diverse and activity. processes including regulation of transcription, chroma- This review focuses on recent advances in our under- tin structure, and DNA repair. Similar to nonproteolytic standing of SUMO function and regulation, drawing on a roles of ubiquitin, SUMO modification regulates protein limited set of examples relating to gene expression, chro- localization and activity. Some proteins can be modified matin structure, and DNA repair. Comparison of SUMO by SUMO and ubiquitin, but with distinct functional and ubiquitin activities in the nucleus reveals interest- consequences. It is possible that the effects of ubiquiti- ing differences in function and suggests surprising simi- nation and SUMOylation are both largely due to binding larities in mechanism. Thus, for example, modification of proteins bearing specific interaction domains. Both of transcription factors and histones by ubiquitin is gen- modifications are reversible, and in some cases dynamic erally associated with increased gene expression whereas cycles of modification may be required for activity. Stud- modification of transcription factors and histones by ies of SUMO and ubiquitin in the nucleus are yielding SUMO is generally associated with decreased gene ex- new insights into regulation of gene expression, genome pression. In some cases, SUMO and ubiquitin may di- maintenance, and signal transduction. -
Intricate SUMO-Based Control of the Homologous Recombination Machinery
Downloaded from genesdev.cshlp.org on September 24, 2021 - Published by Cold Spring Harbor Laboratory Press REVIEW Intricate SUMO-based control of the homologous recombination machinery Nalini Dhingra and Xiaolan Zhao Molecular Biology Department, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA The homologous recombination (HR) machinery plays regulation in mammalian cells and highlight their simi- multiple roles in genome maintenance. Best studied in larities and differences with those found in yeast. It is the context of DNA double-stranded break (DSB) repair, noteworthy that SUMO plays important roles in modulat- recombination enzymes can cleave, pair, and unwind ing protein recruitment to damaged chromatin and in oth- DNA molecules, and collaborate with regulatory proteins er DNA break repair pathways. As these topics have been to execute multiple DNA processing steps before generat- well covered in other reviews (Schwertman et al. 2016; ing specific repair products. HR proteins also help to cope Garvin and Morris 2017), they are not addressed here in or- with problems arising from DNA replication, modulating der to maintain the focus on the regulation of core HR impaired replication forks or filling DNA gaps. Given machinery. these important roles, it is not surprising that each HR step is subject to complex regulation to adjust repair effi- ciency and outcomes as well as to limit toxic intermedi- Overview of the SUMO pathway and the effects ates. Recent studies have revealed intricate regulation of of sumoylation all steps of HR by the protein modifier SUMO, which SUMO, a small protein of ∼100 residues, is highly con- has been increasingly recognized for its broad influence served among eukaryotes with several isoforms found in in nuclear functions. -
Abstract Book
Abstract book WELCOME Dear participants, welcome to the 2010 International PhD Students Cancer Conference here at the IFOM-IEO Campus in Milan! We have tried to organize this conference at our best, hoping it will be an excellent opportunity to discuss about science, to meet new and interesting people and to broad our knowledge. We are very glad to host such an international meeting, with students coming from institutes all across Europe; moreover, this year we are very pleased to host students from the National Centre for Biological Sciences, Bangalore, India. We do hope you will find this conference really exciting and that you will have a great time here in Milan! Thank you all for coming!! The Organizers FOR ORGANIZATION REASONS, YOU ARE KINDLY REQUESTED TO ALWAYS WEAR/SHOW THE CONFERENCE BADGE! THANK YOU VERY MUCH FOR YOUR COLLABORATION! Federica Castellucci: [email protected] Francesca Milanesi: [email protected] Gianmaria Sarra Ferraris: [email protected] Chiara Segrè: [email protected] Gianluca Varetti: [email protected] International PhD Student Cancer Conference International PhD Student Cancer Conference 19th – 21st May 2010 IFOM-IEO Campus, Milan, Italy This is the fourth annual conference that is hosted and organized by students from the European School of Molecular Medicine (SEMM). The Conference will cover many topics related to cancer, from basic biology to clinical aspects of the disease. All attendees will present their research, by either giving a talk or presenting a poster. This conference is an opportunity to introduce PhD students to top cancer research institutes across Europe. -
Enzymes Are Manufactured and Used by Bacteria in Order to Digest Waste
Website: www.fermentor.co.in Food Beverages Textile Leather Agriculture Bio Pharma Effluent Treatment Enzyme : INTRODUCTION Protecting ecology is our duty. We are thus protecting our future generation. Waste water treatment has assumed great significance in today’s context where protecting the environment is a prime concern. The main objective of waste water treatment is to treat the effluent before it is discharged so that the environment is not polluted. Waste water treatment in general refers to treatment of suspended and floatable material, treatment of biodegradable organics and the elimination of pathogenic organisms. The contaminants in waste water are removed by physical chemical and biological means. These organisms are effectively removed by an enzyme called ENVIRO NZYME. ROLE OF AN ENZYME? An enzyme is a chemical catalyst that breaks up long, complex waste molecules (Hydrolytic reaction) into smaller pieces, which can then be digested directly by the bacteria. Enzymes are manufactured and used by bacteria in order to digest waste. ENVIRO NZYME – G a dry free flowing powder is a concentrated source of hydrolytic enzymes and eight strains of natural bacteria that are genetically capable of producing concentrations of enzymes in waste treatment systems under aerobic and anaerobic conditions. ENVIRO NZYME –G is used for reducing the BOD, COD levels as well as reducing the sludge volumes odour and colour in the effluent and sewage treatment plants. APPLICATION: This product finds application in industries like Agro Breweries & -
The Role of Sumoylation of DNA Topoisomerase Iiα C-Terminal Domain in the Regulation of Mitotic Kinases In
SUMOylation at the centromere: The role of SUMOylation of DNA topoisomerase IIα C-terminal domain in the regulation of mitotic kinases in cell cycle progression. By Makoto Michael Yoshida Submitted to the graduate degree program in the Department of Molecular Biosciences and the Graduate Faculty of the University of Kansas in partial fulfillment of the requirements for the degree of Doctor of Philosophy. ________________________________________ Chairperson: Yoshiaki Azuma, Ph.D. ________________________________________ Roberto De Guzman, Ph.D. ________________________________________ Kristi Neufeld, Ph.D. _________________________________________ Berl Oakley, Ph.D. _________________________________________ Blake Peterson, Ph.D. Date Defended: July 12, 2016 The Dissertation Committee for Makoto Michael Yoshida certifies that this is the approved version of the following dissertation: SUMOylation at the centromere: The role of SUMOylation of DNA topoisomerase IIα C-terminal domain in the regulation of mitotic kinases in cell cycle progression. ________________________________________ Chairperson: Yoshiaki Azuma, Ph.D. Date approved: July 12, 2016 ii ABSTRACT In many model systems, SUMOylation is required for proper mitosis; in particular, chromosome segregation during anaphase. It was previously shown that interruption of SUMOylation through the addition of the dominant negative E2 SUMO conjugating enzyme Ubc9 in mitosis causes abnormal chromosome segregation in Xenopus laevis egg extract (XEE) cell-free assays, and DNA topoisomerase IIα (TOP2A) was identified as a substrate for SUMOylation at the mitotic centromeres. TOP2A is SUMOylated at K660 and multiple sites in the C-terminal domain (CTD). We sought to understand the role of TOP2A SUMOylation at the mitotic centromeres by identifying specific binding proteins for SUMOylated TOP2A CTD. Through affinity isolation, we have identified Haspin, a histone H3 threonine 3 (H3T3) kinase, as a SUMOylated TOP2A CTD binding protein. -
AP Biology: Chemistry B Mcgraw Hill AP Biology 2014-15 Contents
AP Biology: Chemistry B McGraw Hill AP Biology 2014-15 Contents 1 Carbohydrate 1 1.1 Structure .................................................. 1 1.2 Monosaccharides ............................................. 2 1.2.1 Classification of monosaccharides ................................ 2 1.2.2 Ring-straight chain isomerism .................................. 3 1.2.3 Use in living organisms ...................................... 3 1.3 Disaccharides ............................................... 3 1.4 Nutrition .................................................. 4 1.4.1 Classification ........................................... 5 1.5 Metabolism ................................................ 5 1.5.1 Catabolism ............................................ 5 1.6 Carbohydrate chemistry .......................................... 5 1.7 See also .................................................. 6 1.8 References ................................................. 6 1.9 External links ............................................... 7 2 Lipid 8 2.1 Categories of lipids ............................................ 8 2.1.1 Fatty acids ............................................. 8 2.1.2 Glycerolipids ........................................... 9 2.1.3 Glycerophospholipids ....................................... 9 2.1.4 Sphingolipids ........................................... 9 2.1.5 Sterol lipids ............................................ 10 2.1.6 Prenol lipids ............................................ 10 2.1.7 Saccharolipids .......................................... -
Paraneoplastic Neurological and Muscular Syndromes
Paraneoplastic neurological and muscular syndromes Short compendium Version 4.5, April 2016 By Finn E. Somnier, M.D., D.Sc. (Med.), copyright ® Department of Autoimmunology and Biomarkers, Statens Serum Institut, Copenhagen, Denmark 30/01/2016, Copyright, Finn E. Somnier, MD., D.S. (Med.) Table of contents PARANEOPLASTIC NEUROLOGICAL SYNDROMES .................................................... 4 DEFINITION, SPECIAL FEATURES, IMMUNE MECHANISMS ................................................................ 4 SHORT INTRODUCTION TO THE IMMUNE SYSTEM .................................................. 7 DIAGNOSTIC STRATEGY ..................................................................................................... 12 THERAPEUTIC CONSIDERATIONS .................................................................................. 18 SYNDROMES OF THE CENTRAL NERVOUS SYSTEM ................................................ 22 MORVAN’S FIBRILLARY CHOREA ................................................................................................ 22 PARANEOPLASTIC CEREBELLAR DEGENERATION (PCD) ...................................................... 24 Anti-Hu syndrome .................................................................................................................. 25 Anti-Yo syndrome ................................................................................................................... 26 Anti-CV2 / CRMP5 syndrome ............................................................................................